Cellular and Molecular Mechanisms Mediating Histamine's Neuromodulator Role in the Paraventricular Hypothalamus.

组胺在中枢神经系统(CNS)中具有神经调节作用，可通过脑内表达的三种不同的组胺受体(H1R、H2R、H3R)影响神经传递。组胺能神经元位于下丘脑后部，向下丘脑多个核团发送密集的投射，帮助协调这些核团的输出反应。有一种激素的反应被认为可以被组胺能系统改变，那就是瘦素，这是一种从脂肪组织分泌的荷尔蒙，以下丘脑的神经元为靶标。然而，组胺能系统调节瘦素在中枢神经系统中的作用的机制仍有待确定。此外，组胺和瘦素信号在特定的下丘脑神经元群中汇聚的可能性以前还没有被解决。我的研究计划的主要目标是确定组胺能系统如何整合和调节不同的体内平衡信息，并确定它所在的大脑区域。作为这个总体目标的一部分，我的研究计划的短期目标是确定神经位置和机制，将能量状态的激素信号，如瘦素，和大脑中的组胺能信号联系起来。我的初步数据表明，瘦素上调H1R基因的表达，H1R在下丘脑室旁核(PVH)强烈表达，这是瘦素作用的主要靶点。此外，H1R与促肾上腺皮质激素释放(CRH)神经元在PVH的同一区域表达，CRH神经元先前被认为与下丘脑中的组胺和瘦素的作用有关。在这里，我建议使用神经科学、药理学和分子遗传学的方法来梳理组胺影响CRH-PVH神经元活动的机制。基于我以前在膜片钳电生理学和组胺能系统方面的工作和专业知识，本项目旨在：1)确定组胺受体1(H1R)和2(H2 R)对CRH神经元电兴奋性的贡献；2)确定组胺受体诱导的CRH神经元兴奋是通过直接机制还是间接机制发生的；3)确定组胺是否增加了瘦素介导的CRH神经元的兴奋。由于之前已经在组胺能系统和下丘脑中发现了性别差异，我们也将探索性别对这些神经元反应的影响。这项发现拨款将提供全面的机械见解，了解组胺如何通过两种不同的组胺受体调节CRH神经元的电兴奋性，并使我们能够开始阐明组胺调节瘦素中枢作用的大脑区域和细胞。总而言之，这项工作将促进我们对组胺在大脑中的神经调节作用的理解，并将为参与其中的学生提供强大的培训体验。

Histamine exhibits a neuromodulator role in the central nervous system (CNS) and can influence neurotransmission via 3 different histamine receptors expressed in the brain (H1R, H2R, H3R). The histaminergic neurons are located in the posterior hypothalamus and send dense projections to multiple hypothalamic nuclei where they help to coordinate the output responses from these nuclei. One hormone's response that has been suggested to be modified by the histaminergic system is that of leptin, a hormone secreted from the adipose tissue that targets neurons in the hypothalamus. However, the mechanisms by which the histaminergic system regulates the actions of leptin in the CNS remain to be determined. Moreover, the potential for convergence of histamine and leptin signaling within specific hypothalamic neuronal populations has not been previously addressed. The main goal of my research program is to determine how the histaminergic system integrates and regulates different homeostatic information, and to identify the brain regions in which it does so. As part of this overarching goal, the short-term objective of my research program is to determine the neural sites and mechanisms linking hormonal signals of energy status, such as leptin, and histaminergic signaling in the brain. My preliminary data suggests that leptin upregulates H1R gene expression, and that H1R is strongly expressed in the paraventricular nucleus of the hypothalamus (PVH), which is a major target of leptin's actions. Moreover, the H1R is expressed in the same region of the PVH as the corticotrophin releasing (CRH) neurons which have previously been implicated in linking histamine and leptin actions in the hypothalamus. Here, I propose to use neuroscience, pharmacology, and molecular genetic approaches to tease apart the mechanisms by which histamine influences the activity of CRH PVH neurons. Building upon my previous work and expertise in patch-clamp electrophysiology and the histaminergic system, this program aims to: 1) determine the contribution of the histamine receptor 1 (H1R) and 2 (H2R) to CRH neuron electrical excitability; 2) determine if histamine receptor-induced excitation of CRH neurons occurs by direct or indirect mechanisms; 3) determine if histamine increases the leptin-mediated excitation of CRH neurons. As sex differences have previously been demonstrated in the histaminergic system and the hypothalamus, we will also explore the impact of sex on these neuronal responses. This Discovery Grant will provide comprehensive mechanistic insights into the way in which histamine regulates CRH neuron electrical excitability via two distinct histamine receptors and will allow us to start to elucidate the brain regions and cells where histamine regulates leptin's central actions. Together this work will advance our understanding of histamine's neuromodulator role in the brain and will provide a formidable training experience for the students involved.